This invention relates to benzo[b]quinolizidines, be U[f]indolizidines, and ring-expanded derivatives thereof, which are useful for the treatment of neurodegenerative states and diseases associated with memory impairment. The invention also relates to pharmaceutical compositions comprising these compounds, and to methods of treating or controlling the symptoms of Alzheimer""s disease, senile dementia, or other conditions associated with the impairment of memory. The compounds of this invention are weak inhibitors of neural acetylcholinesterase in vitro. The compounds of this invention also protect rodents against scopolamine-induced amnesia without inducing psychomotor or behavioral deficits.
Impairment of cognition and memory is associated with numerous diseases. The most widely known is Alzheimer""s disease, which is associated with extensive loss of specific neuronal subpopulations in the brain (Sims, N. R., et al. (1987) Annals of Neurology 21:451; Katzman, R. (1986) New England Journal of Medicine 314:964). The biochemical and cellular changes which lead to neuronal loss remain unknown. Proposed causes include environmental factors, (Perl, D. P. (1985) Environmental Health Perspective 63:149; Katzman, R. (1986)), including metal toxicity, (Perl, D. P., et al. (1980) Science 208:297), defects in xcex2-amyloid protein metabolism; (Shoji, M., et al. (192) Science 253:126; Assoc. Disord. 6:7; Kosik, K. S. (1992) Science 256:780; Selkoe, D. J. (1991) Neuron 6:487; Hardy, H. and Allsop, D. (1991) Trends in Pharmacological Science 12:383; Varghese, J., et al., 1997, Annual Reports in Medicinal Chemistry 32:11), and abnormal calcium homeostasis and/or calcium activated kinases. (Mattson, M. P., et al. (1992) Journal of Neuroscience 12:376; Borden, L. A., et al. (1991) Neurobiology of Aging 13:33; Peterson, E., et al. (1989) Annals of New York Academy of Science 568:262; Peterson, C., et al. (1988) Neurobiology of Aging 9:261; Peterson, C., et al. (1986) Proceedings of the National Academy of Science 83:7999).
Tacrine hydrochloride (COGNEX) was the first drug approved for the treatment of Alzheimer""s Disease. Tacrine is a complex pharmacological agent (Cacabelos, R., et al., Drugs of Today 1994, 30, 295) which among other properties is a potent inhibitor of acetylcholinesterase (AcChE), and an even more potent inhibitor of the butyrylcholinesterase family of enzymes (Maayani, S., et al., Biochem. Pharmacol. 1974, 23, 1263-1281). Tacrine is generally considered to be a postsynaptic agent (Hershenson, F. M. in New Leads and Targets in Drug Research, Alfred Benzon Symposium 33, pages 354-363, ed. P. Krogsgaard-Larsen, S. Brogger, H. Kofod; Munksgaard, Copengagen, 1992). Other synaptic AcChE inhibitors include the tacrine analogs, physostigmine (Drugs of the Future 1991, 16, 33; ibid. 1994, 19, 343, 656) and physostigmine derivatives, E-2020 (Drugs of the Future 1991, 16, 33; ibid. 1994, 19, 343, 656), and huperzine A (Drugs of the Future 1991, 16, 33; ibid. 1994, 19, 343, 656).
Tacrine belongs to the well-known structural class of aminopyridines (Osterrieder, W. Br. J. Pharmac. 1987, 92, 521; Edwards, G. and Weston, E. H. in Receptor Data for Biological Experiments, p. 194, Ellis Horwood, N.Y., 1991) which are potassium channel blockers. The deficiency of tacrine as a drug is related to its liver toxicity and peripheral cholinomimetic actions (Manning, F. C. American Family Physician 1994, 50, 819).
Many analogs of tacrine have been prepared (Drugs of the Future 1991, 16, 33; ibid. 1994, 19, 343, 656; McKenna, M., et al., J. Med. Chem. 1997, 40, 351-3523). Because the 4-aminoquinoline portion of tacrine is generally believed to be important for binding of the drug to the active site of AcChE (Silman, I., et al., Biochem. Soc. Trans., 1994, 22, 745-749), most of these are structurally related to the parent compound, and tend to exhibit some of the same toxicological problems as tacrine. Consequently, there remains a great need for alternative drugs, less structurally related to tacrine, for the treatment of memory impairment such as is associated with Alzheimer""s disease.
The systematic name for the benzo[b]quinolizidine ring system is 1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizine. Although the parent ring system has been known for some time, derivatives with an amino group at C-11 were not previously known.
With respect to 11-oxygenated derivatives, the C-11 ketone (1,3,4,11a-tetrahydro-2H-benzo[b]quinolizin-11(6H)-one) is known (G. Gonzalez Trigo and J. Alvarez-Builla, An. Quim., Ser. C, 1980, 76: 12-15), as is the 8,9-dimethoxy derivative (Sugimoto, Yakugaku Zasshi (J. Pharm. Soc. Japan), 1956, 76, 1045; Chem. Abstr. 1957, 3598). The 11-hydroxy derivative (1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizin-11-ol) is known (G. Gonzalez Trigo and J. Alvarez-Builla, loc. cit.), as are some 11-aryl and 11-aminoalkyl derivatives (G. E. Hardtnann, U.S. Pat. No. 3,408,352; W. Houlihan and J. Nadelson, U.S. Pat. 3,824,244 and 3,892,752) and the 8,9-dimethoxy derivative (S. Kupchan et al., J. Org. Chem., 1966, 31:1713-1716).
The systematic name for the benzo[f]indolizidine ring system is 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinoline. Although the parent ring system has been known for some time, derivatives with an amino group at C-10 have not been reported previously.
With respect to 11-oxygenated derivatives, 1,2,3,5,10,10a-hexahydropyrrolo[1,2-b]isoquinolin-10-ol is known (Totleben, M. J., et al., J. Org. Chem., 1997, 62:7319-7323; Rigo, B.; Kolocouris, N. J. Heterocyclic. Chem. 1983, 20:893-898), as is the 7,8-dimethoxy derivative, and the 10-O-acetate ester thereof (Knefeli, F., et al., Arch. Pharm., 1983, 316:773-781).
A few 3-keto derivatives of the 10-hydroxy compound are also known (Rigo, B., and Kolocouris, N., loc. cit.,; Kubo, A., et al., Heterocycles, 1966, 42:195-211.
In general this invention relates to benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives thereof, and to pharmacological compositions containing these compounds. The compounds of the present invention are benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives of the general formula: 
wherein m, n, p, R1, R3, R4, R6 and R7 are as defined further below.
The compounds of this invention are expected to be useful for enhancing cognition, and for treating or controlling the symptoms of memory impairment in senile dementia, Alzheimer""s disease, or similar conditions. Although some of these conditions may be associated with decreased availability of acetylcholine, and although the compounds of this invention are in general weak inhibitors of acetylcholinesterase, the present invention is not limited with regard to any specific mechanism of action, nor are the memory-enhancing properties of the compounds of the invention attributed to any specific mechanism.
The present invention provides benzoquinolizidines, benzoindolizidines, and ring-expanded derivatives thereof, wherein a tetrahydroisoquinoline is fused to a pyrrolidine, piperidine, azepine or azocine ring. These compounds are of the general formula: 
wherein n=1 to 4, and each R1 independently may be hydrogen, halo, or optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, trifluoromethyl, cyano, carboalkoxy, alkanoyl, aroyl, or alkylsulfonyl;
wherein R2=OR5 or NR6R7, and R5 is hydrogen, optionally substituted alkyl or cycloalkyl, alkanoyl, aroyl, aryl, arylalkyl, alkylaryl, haloalkyl, or haloalkoxy, and R6 and R7 may each independently be hydrogen, optionally substituted alkyl or cycloalkyl, aryl, arylallyl, alkylaryl, aroyl, alkanoyl, alkylaroyl, or arylalkanoyl, or NR6R7 may be azetidino, pyrrolidino, piperidino, or morpholino;
wherein p=1 to 6, and R3 is hydrogen, hydroxy, alkoxy, halo, optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, alkylaryl, haloallyl, haloalkoxy;
wherein R4 is hydrogen, optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, alkylaryl, haloalkyl, or haloalkoxy; and
wherein m=1 to 4.
Halo includes bromo, iodo, fluoro or chloro; preferably chloro, bromo or fluoro; and most preferably is chloro or fluoro.
The term xe2x80x9calkylxe2x80x9d, alone or in combination, is intended to include straight chain and branched alkyl groups containing from 1 to about 10 carbons, preferably from 1 to about 8 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, amyl, isoamyl, hexyl, octyl and the like.
The term xe2x80x9ccycloalkylxe2x80x9d, alone or in combination, is intended to include a saturated or partially saturated monocyclic alkyl radical which contains from 3 to about 8 carbon atoms. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 3-cyclohexenyl, cycloheptyl, cyclooctyl, and the like.
The term xe2x80x9carylxe2x80x9d, used alone or in combination, is intended to include an aromatic hydrocarbon which may be monocyclic, bicyclic, or tricyclic, such as phenyl, naphthyl, or anthryl, which optionally carries one or more substituents selected from alkyl, alkanoyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, alkylsulfonyl, haloalkyl and the like. Examples include p-tolyl, 4-ethoxyphenyl, 4-(t-butoxy)phenyl, 4fluorophenyl, chlorophenyl, 4-acetylphenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, and the like.
The term xe2x80x9carylalkylxe2x80x9d, alone or in combination, is an alkyl as defined above in which one hydrogen atom is replaced by an aryl radical as defined above, such as for example benzyl, 2-phenylethyl, and the like.
The term xe2x80x9chaloalkylxe2x80x9d is intended to include an alkyl radical having the significance as defined above wherein one or more hydrogens are replaced with a halogen. Examples of such haloalkyl radicals include, but are not limited to, chloromethyl, 2-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like.
The terms xe2x80x9ccisxe2x80x9d and xe2x80x9ctransxe2x80x9d refer to the stereochemical relationship between the benzylic substituent (in the benzo[b]quinolizidines, on C-11) and the bridgehead hydrogen (in the benzo[b]quinolizidines, on C-11a). The corresponding positions in the benzo[f]indolizidines are at C-10 and C-10a. The sterochemistry of the compounds may be readily determined from the 1H NMR spectra. The trans isomers are characterized by a coupling constant of 1 to 3 Hz between the H-11 and H-11a, whereas the cis isomers are characterized by a coupling constant of 8 to 11 Hz.
Examples of optional substituents include, but are not limited to, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkoxy, halogen, hydroxy, amino, nitro, cyano, alkylsulfonyl, haloalkyl, and the like. The optional substituents may themselves be optionally substituted, for example R1 may be 3-chlorobenzyloxy or the like.
Heteroaryl refers to an aromatic group of from 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g., pyridyl, tetrazolyl, or furyl) or multiple condensed rings (e.g., indolyl, quinolyl, or benzothienyl), which can optionally be unsubstituted or substituted with hydroxy, alkyl, alkoxy, halo, mercapto, and the like. Preferred heteroaryls include for example pyridyl and furyl.
The term alkanoyl refers to an alkyl group as defined above, attached to a carbonyl group, and the term aroyl refers to an aryl group as defined above, attached to a carbonyl group.
Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers thereof where such isomers exist, as well as pharmaceutically acceptable acid addition salts thereof and solvates thereof such as, for instance, hydrates. Separate enantiomeric forms or racemic mixtures of the compounds are also within the scope of this invention.
Preferred compounds of the invention conform to the following formulae: 
wherein R1 through R7, m, n and p are as described above. More preferably, m is 1 or 2. Preferred compounds include the following:
R1 is H, R3 is H, R4 is H, R6 is H, R7 is H and m is 2 (trans-1,3,4,6,11,11a-hexahydro-11-amino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 2 (trans-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is benzyl, and m is 2 (trans-1,3,4,6,11,11a-hexhydro-11-benzylamino-2H-benzo[b]quinolizine);
R1 is 9-methoxy, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 2 (trans-9-methoxy-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is 9-methoxy, R3 is H, R4 is H, R6 is H, R7 is benzyl and m is 2 (trans-9-methoxy-1,3,4,6,11,11a-hexahydro-11-benzylamino-2H-benzo[b]quinolizine);
R1 is 8-chloro, R3 is H, R4 is H, R6 is H, R7 is methyl and m is 2 (trans-8-chloro-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 1 (cis-1,2,3,5,10,10a-hexahydro-10-(methylamino)-pyrrolo[1,2-b]isoquinoline);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is alkanoyl and m is 2 (trans-1,3,4,5,11,11a-hexahydro-11-alkanoylamino-2H-benzo[b]quinolizine); and
R1 is H, R3 is H, R4 is H, R6 is H, R7 is n-butyryl and m is 2 (trans-1,3,4,5,11,11a-hexahydro-11-butyrylamino-2H-benzo[b]quinolizine).
Preferably, when m is 2, the compounds are in the trans configuration, as shown in Formula 2.
Other compounds of the invention conform to the following formulae: 
wherein R1 through R5, m, n and p are as described above.
In a preferred embodiment, R1 is H and n is 1, R3 is H and p is 4, R4 is H, R5 is alkanoyl, such as acetyl or propionyl, and m=2.
When m is 2, the compound is preferably in the trans configuration as in formula 4.
The compounds of formula 1 can be prepared by the following methods. Compounds of the formula 6 can be converted to compounds of general formula 1 via an imine intermediate 7 or via an alcohol intermediate 8. 
The starting ketone 6 can be prepared according to the literature (Gonzalez Trigo, G.; Alvarez-Builla, J. An. Quim., Ser. C 1980, 76, 12). Accordingly, an ethyl pipecolinate hydrochloride 9 can be allowed to react with a substituted benzyl chloride in the presence of a base, for example, potassium carbonate (K2CO3), sodium carbonate (Na2CO3), or lithium carbonate, (Li2CO3). The resulting ester 11 can be hydrolyzed, for example with concentrated hydrochloric acid, to an acid 12 which can be cyclized under Friedel-Craft conditions, for example with aluminum chloride. polyphosphoric acid (PPA), or phosphorous pentoxide in methanesulfonic acid (Eaton""s reagent), to give the ketone 6. 
The reductive amination of ketone 6 can be accomplished by reaction of the ketone 6 with an amine in an organic solvent, preferably in the presence of a catalyst and dehydrating agent, such as for example titanium tetrachloride (TiCl4). The solvent can then be removed by conventional methods, including but not limited to evaporation in vacuo. After the reaction of the ketone with the amine, the resultant imine 7 is reduced with a reducing agent such as, for example, sodium cyanoborohydride, lithium aluminum hydride (LAH), or by catalytic hydrogenation, to give the desired amine as the trans isomer 2. 
The cis isomer 3 can be obtained by a dissolving metal reduction of imine 7, for example by reduction with sodium metal in ethanol. Reaction with sodium in ethanol appears generally to favor the thermodynamically more stable product 3 as the major isomer (Rausser, R.; Weber, L.; Hershberg, E. B.; Oliveto, E. P. J. Org. Chem. 1966, 31, 1342-1346). 
The trans N-benzyl derivatives (2, R6=benzyl) can be prepared via an N-benzyl imine (for example 7, R6=benzyl) by hydrogenation under neutral conditions.
When the benzylamino derivative is subjected to further hydrogenation in the presence of an acid, as for example hydrochloric acid, the benzyl group is cleaved to give a trans primary amine (2, R6=H). 
The cis isomer, when R6 and R7 are both H (3, R6=H), can be obtained from the xcex1-(methyl)benzylimine intermediate 7b (Bolton, R.; Danks, T. N.; Paul, J. M. Tetrahedron Lett. 1994, 35, 3411) which can he reduced, for example with sodium borohydride, to secondary amine 3b and then hydrogenolyzed, for example with palladium on carbon, to give a primary cis amine 3a.
A single enantiomer of xcex1-(methyl)benzylamine may be employed, and separation of the diasteromers of 3b, for example by chromatography, may be carried out, so as to obtain a single enantiomer of 3a upon hydrogenolysis. A similar procedure will provide the trans enantiomers (2, R6=H).
Ketone 6 may also be hydrogenated, for example with palladium on carbon in tetrahydrofuran and hydrochloric acid, to provide the cis and trans alcohols 12 and 8, which may then be converted to the corresponding esters, for example the acetates 13 and 14, by treatment with an acyl chloride or anhydride in the presence of a base such as pyridine, 4-(dimethylamino)pyridine, and/or triethylamine. 
Amide derivatives of structure 16 can also be synthesized by the acylation of 15 with an acyl chloride or anhydride in the presence of a base such as pyridine, 4-(dimethylamino)pyridine, and/or triethylamine. 
A particular amide which may be synthesized is derived from 2-oxo-1-pyrrolidineacetic acid 18. The reaction of 18 and 2a in the presence of carbonyl diimidazole (CDI) gives the amide 19. 
An alternative method for synthesizing compounds of the formula 2 is as follows. Pyrrolidinonecarboxylic acid 21 can be converted to a ketone 22 (Rigo, B.; Kolocouris, N. J. Heterocyclic. Chem. 1983, 20, 893). The ketone can then be converted to imine 23, and the imine can be hydrogenated to give trans amino-ketone 24, with the amide carbonyl intact. Alternatively, borohydride reduction of 23 provides the corresponding cis amino-ketone. Reduction of 23 or 24, for example by lithium aluminum hydride or borane, is also expected to reduce the amide carbonyl of 24 to provide compounds of structure 2 (see the preparation of 32 below). 
The pyrrolidinonecarboxylic acid 21 can be synthesized by a multi-step procedure described in the literature (Buckley III, T. F.; Rapoport, H. J. Org. Chem. 1984, 48, 4222), with modifications. Thus; an optionally subsituted d,l-glutamic acid 26 is esterified, for example with isopropanol in the presence of sulfuric acid. The resulting ester 27 is benzylated on nitrogen by reaction with an arylmethyl halide, such as benzyl chloride, in the presence of a base such as potassium carbonate. Cyclization of the resulting compound 28 can be carried out by mild heating under acidic conditions, for example in methanol and acetic acid, to give a pyrrolidinone ester 29. The acid 21 is obtained by the saponification of ester 29. 
Alternatively, acid 21 can be prepared from d,l-glutamic acid by modification of a two step procedure described in the literature (Ohfune, Y.; Kurokawa, N.; Higuchi, N.; Saito, M.; Hashimoto, M.; Tanaka, T. Chem Let. 1984, 441; and Peterson, J. S.; Fels, G.; Rapoport, H. J. Am. Chem. Soc. 1984, 106, 4539). Specifically, the reductive amination of d,l-glutamic acid with NaBH3CN in the presence of benzaldehyde gave N-benzylated glutamic acid 20 (R4=H). Acid 21 (R4=H) was obtained by heating 20 in water. 
An alternative strategy to prepare compounds of structure 6 (m=1) involves the initial reduction of the amide carbonyl of compound 22. As reported (Rigo, B.; Kolocouris, N. J. Heterocyclic. Chem. 1983, 20, 893), ketone 22 was first protected as ketal 31 which was then subjected to LAH reduction. 
The resulting ketal 32 was deprotected under acidic conditions to give ketone 33 (Rigo, B.; Kolocouris, N., J. Heterocyclic. Chem. 1983, 20, 893). Compound 33 can then be converted, by the methods described herein, to imine 34 and then to amine derivative 35.
Yet another method for synthesizing ketone 33 is by reduction of the ketone 22 to alcohol 36 (Rigo, B.; Kolocouris, N. J. Heterocyclic. Chem. 1983, 20, 893) which can then be oxidized to ketone 37 (Szmuszkovicz, J.; Skaletzky, L. L. J. Org. Chem. 1967, 32, 3300). 
This invention also provides methods of treating or controlling disease states characterized by the symptom of memory loss, such as Alzheimer""s disease, senile dementia, or similar conditions, comprising administering a therapeutically effective amount of at least one of the compounds of the present invention, pharmaceutically-acceptable salts thereof, or mixtures thereof.
Compounds to be administered may have the general formula: 
wherein n=1 to 4, and each R1 independently may be hydrogen, halo, or optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, trifluoromethyl, cyano, carboalkoxy, alkanoyl; or alkylsulfonyl;
wherein R2=OR5 or NR6R7, and R5 is a hydrogen or optionally substituted alkyl, cycloalkyl, alkanoyl, aryl, arylalkyl, arylakyl, haloalkyl, or haloalkoxy; and R6 and R7 may each independently be hydrogen or optionally substituted alkyl, cycloalkyl, aryl, arylalkyl or alkylaryl or optionally substituted alkyl carbonyl, alkylaryl carbonyl, or NR6R7 may be azetidino, pyrolidino, piperidino, or morpholino;
wherein p=1 to 6, and R3 is hydrogen, hydroxy, alkoxy, halo, optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, alkylaryl, haloalkyl, haloalkoxy;
wherein R4 is hydrogen, optionally substituted alkyl or cycloalkyl, aryl, arylalkyl, alkylaryl, haloalkyl, or haloalkoxy; and
wherein m=1 to 4.
In certain preferred embodiments of the invention, the compounds to be administered conform to the following formulae: 
wherein
R1 is H, R3is H, R4is H, R6is H, R7is H and m is 2 (trans-1,3,4,6,11,11a-hexahydro-11-amino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 2 (trans-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is benzyl, and m is 2 (trans-1,3,4,6,11,11a-hexhydro-11-benzylamino-2H-benzo[b]quinolizine);
R1 is 9-methoxy, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 2 (trans-9-methoxy-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is 9-methoxy, R3 is H, R4 is H, R6 is H, R7 is benzyl and m is 2 (trans-9-methoxy-1,3,4,6,11,11a-hexahydro-11-benzylamino-2H-benzo[b]quinolizine);
R1 is 8-chloro, R3 is H, R4 is H, R6 is H, R7 is methyl and m is 2 (trans-8-chloro-1,3,4,6,11,11a-hexahydro-11-methylamino-2H-benzo[b]quinolizine);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is methyl, and m is 1 (cis-1,2,3,5,10,10a-hexahydro-10-(methylamino)-pyrrolo[1,2-b]isoquinoline);
R1 is H, R3 is H, R4 is H, R6 is H, R7 is alkanoyl and m is 2 (trans-1,3,4,5,11,11a-hexahydro-11-alkanoylamino-2H-benzo[b]quinolizine); and
R1 is H, R3 is H, R4 is H, R6 is H, R7 is n-butyryl and m is 2 (trans-1,3,4,5,11,11a-hexahydro-11-butyrylamino-2H-benzo[b]quinolizine).
Preferably, when m is 2, the compounds are in the trans configuration, as shown in Formula 2.
In other preferred embodiments of the invention, the compounds to be administered conform to the following formulae: 
wherein
R1 is H, R3is H, R4is H, R5is H, and m is 2 (trans-1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizidin-11-ol),
R1 is H, R3 is H, R4 is H, R5 is alkanoyl, and m is 2 (O-alkanoyl-trans-1,3,4,6,11,11a-hexahydro-2H-benzo[b]quinolizidin-11-ol).
More preferably, R5 is acetyl, and preferably the compounds are in the trans configuration as shown in formula 4.
The activity associated with the compounds of this invention may be determined based on an in vitro assay or an in vivo assay. By way of example, an in vitro technique that may be used includes, but is not limited to, assessment of inhibition of acetylcholinesterase activity in the presence of the compounds of this invention. Accordingly, acetylcholinesterase activity is assessed in the presence of varying concentrations of the compound of the invention. The preferred compounds are capable of inhibiting acetylcholinesterase activity in vitro.
Alternatively, the activity associated with the compounds of this invention may be assessed by an in vivo assay such as the reversal or antagonism of scopolamine-impaired passive avoidance learning. Preferred compounds are capable of reversing the impairment of learning induced by administered scopolamine.
An effective amount of the compounds of this invention is a dosage sufficient to control or alleviate the symptoms of the disease state or condition of the subject. The dosage of the compounds of this invention will vary depending upon several parameters including, but not limited to, the age of the subject, the severity and type of the disease state, the general health of the subject and other parameters known to one skilled in the art. Based on such parameters the treating physician will determine the therapeutically effective amount of the compound for a given individual. Such therapies may be administered as often as necessary and for the period of time judged necessary by the treating physician. The compounds of the present invention may be administered alone or in combination with other therapies.
Effective quantities of the compounds of the invention may be administered to a patient by any of the various methods, for example, orally as in capsules, tablets, or suspensions; rectally in the form of suppositories; parenterally in the form of sterile solutions or suspensions; and in some cases intravenously in the form of sterile solutions. The free base final products, while effective themselves, may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts for the purposes of stability, convenience of crystallization, increased solubility and the like.
Acids useful for preparing the pharmaceutically acceptable acid addition salts of the invention include inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as well as organic acids such as tartaric, citric, acetic, succinic, maleic, malic, fumaric, oxalic, medhanesulfonic and toluenesulfonic acids.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an edible carrier, or they may be enclosed in gelatin capsules, or they may be compressed into tablets. For the purpose of oral therapeutic administration, the active compounds of the invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum and the like. These preparations may contain about 5 mg to about 200 mg of the active compound, but may be varied depending upon the particular form. The amount of active compound in such compositions is such that a suitable dosage will be obtained.
The tablets, pills, capsules, troches and the like may also contain the following ingredients: a binder such as micro-crystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Promogel, cornstarch and the like; a lubricant such as magnesium stearate or Sterotex; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin may be added or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, for example coatings. Thus tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes, coloring and flavors. Materials used in preparing these various compositions should be pharmaceutically pure and non-toxic in the amounts used.
For the purposes of parenteral therapeutic administration, the active compounds of the invention may be incorporated into a solution or suspension. The amount of active compound in such compositions is such that a suitable dosage will be obtained. The compositions and preparations according to the present invention may be prepared so that a parenteral dosage unit contains between about I mg to about 30 mg of active compound.
The solutions or suspension may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in disposable syringes or multiple dose vials made of glass or plastic.